The family of poly(ADP-ribose)polymerases (PARP) is composed of about 17 proteins, including PARP-1, PARP-2, PARP-3, PARP-4 (vPARP), PARP-5 (tankyrase-1, tankyrase-2), PARP-7, PARP-10 and the like [Curr Pharm Des., 13(9), 933-962, 2007]. These proteins all show a certain level of homology in their catalytic domain but differ in their cellular functions [BioEssays., 26(8), 882-893, 2004].
Among the many functions attributed to PARP-1 and PARP-2, its major role is to facilitate DNA repair by ADP-ribosylation and therefore coordinate a number of DNA repair proteins. Activation of PARP is induced by DNA single strand breaks after exposure to radiation, oxygen free radicals, or nitric oxide (NO), etc. DNA damage leads to PARP activation that repairs DNA single strand breaks, and thus PARP can contribute to resistance that may occur in various types in cancer therapy. Particularly, PARP inhibitors were reported to be useful for specific killing of tumors deficient in DNA double-strand repair factors such as BRCA-1 and BRCA-2, and thus have been developed as patient-specific anticancer agents against various types of cancers, including breast cancer, ovarian cancer, prostate cancer and the like, which have abnormalities in DNA double-strand damage repair factors [Nature, 434, 913-916, 2005; Cancer Biology & Therapy, 4, 934-936, 2005]. In addition, PARP inhibitors, when administered in combination, are known to enhance the efficacy of anticancer drugs that are used in conventional anticancer therapies [Pharmacological Research, 52, 25-33, 2005; Mol Cancer Ther, 2, 371-382, 2003; Clin Cancer Res, 6, 2860-2867, 2000]. Anticancer drugs that enhance the efficacy of PARP inhibitors include platinum compounds (cisplatin and carboplatin), topoisomerase inhibitors (irinotecan and topotecan), and temozolomide, etc.
Furthermore, it is known that inhibition of PARP enhances resistance to brain injury. When cerebral infarction occurs and cerebral blood vessels become clogged, oxygen in the cerebral blood vessels becomes deficient, and at this time, a large amount of glutamate is released and excessively activates glutamate receptor to produce an excessive amount of reactive oxygen species that damage DNA. It is considered that PARP activation caused by DNA damage in cerebral infarction rapidly consumes an excessive amount of NAD+ to deplete energy in brain cells, causing ischemic brain injury [Cereb Blood Flow Metab., 17(11), 1143-1151, 1997]. PARP Inhibitors may be used for treatment of not only ischemic brain injury, but also various neurological diseases and cardiovascular diseases, including epilepsy, stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia, chronic or acute pain, ischemic brain injury, neuronal loss after hypoxia, trauma, and nerve damage.
Furthermore, PARP inhibitors inhibit the production of inducible nitric oxide synthase (iNOS) in macrophages, P-selectin, and intercellular adhesion molecule-1 (ICAM-1) in endothelial cells. This activity becomes the basis of potent anti-inflammatory effects exhibited by PARP inhibitors. In addition, inhibition of PARP can reduce necrosis by preventing the translocation and penetration of neutrophils into damaged tissue. Therefore, PARP inhibitors are also useful for inflammatory symptoms. In recent years, the therapeutic potential of PARP inhibitors for treatment of diabetic neuropathy has been suggested [Diabetes. 54(12), 3435-3441, 2005].
Meanwhile, tankyrase-1 and tankyrase-2, also known as PARP-5, are known to be involved in Wnt/β-catenin signaling pathways, DNA repair processes, and mitosis which is highly related to the cell cycle [Biochimica et Biophysica Acta, 1846, 201-205, 2014]. In addition, tankyrase-1 and tankyrase-2 act as a positive regulator of telomere length that ADP-ribosylates TRF-1 to allow telomerase-mediated telomere elongation. Therefore, inhibition of tankyrase-1 and tankyrase-2 can inhibit Wnt/β-catenin signaling pathways, DNA repair processes and telomere elongation, thereby exhibiting anticancer effects through mechanisms different from those of PARP-1 [Nature Reviews Drug Discovery, 11, 923-936, 2012].
Accordingly, the present inventors have synthesized tricyclic derivative compounds as poly(ADP-ribose)polymerase (PARP)-1 inhibitors or tankyrase inhibitors, which may be used for treatment of various diseases caused by poly(ADP-ribose)polymerase (PARP) activity, and have found that the compounds exhibit excellent activity against PARP-1, tankyrase-1 or tankyrase-2, thereby completing the present invention.